Thioureas are known as substances which accumulate in malignant melanoma due to its active melanin synthesis.
Malignant melanoma is a tumor of melanocytes. Its incidence is especially high among the fair-skinned population. In most industrial nations its incidence is increasing.
Present treatment of melanoma consists of the surgical removal of the primary lesion. According to the histologically determined degree of classification, skin up to and including the regional lymph nodes are removed. Despite this, the five-year survival with melanomas grade II and higher, but also with melanomas grade I with high prognostic index (Kopf, Cancer, 59, 1236, 1987), is poor, as it apparently is not possible to remove all in-transit metastases of the skin and the lymph nodes.
Radiation treatment of the afflicted limbs, in order to sterilize these metastases with or without radical surgery, has not yet been successful (Kynaston, Aust. N.Z. J. Surg., 48, 36, 1978).
The known radiotherapeutic modality of neutron capture therapy utilizes the property of boron-10 (which represents 20% of the naturally occurring nuclide mixture and can be enriched from it) to capture a thermal neutron with high probability, as compared to the other nuclides of the body, and disintegrate upon capture to a helium-4 and a lithium-7 particle. Each of these particles is capable of sterilizing a cell with a single event (Gabel, Radiat. Res. 68, 307, 1984).
Depending on the depth of the tumor and the energy spectrum of the neutron beam, at least 14 ppm boron-10 are necessary in the target tissue, for therapy to be successful, with a tumor-to-surrounding ratio of boron of around 10:1 (Fairchild and Bond, Int. J. Radiation Oncol. Biol. Phys., 11, 831, 1985). For a thermal neutron beam and a tumor depth of 4 cm, tumor therapy is not possible with a boron ratio between tumor and surrounding tissue of 3:1 at any boron concentration; at a ratio of 10:1, 36 ppm boron are necessary.
Neutron capture therapy (NCT) differs from other radiotherapy modalities inasfar as an external beam produces a high radiation dose only where a chemical compound has accumulated prior to irradiation. It differs from other chemotherapy modalities inasfar as the compound accumulated expresses its tumoricidal action only in the field of the beam.
Coderre (Cancer Research, 48, 6313, 1988) has shown that p-dihydroxyborylphenylalanine (BPA) can accumulate physiologically in melanomas. Six hours after intraperitoneal injection, boron concentrations in the tumor of up to 30 ppm were found, with a tumor-to-blood and tumor-to-muscle ratio of around 5:1. After 24 hours, boron concentration in the tumor dropped and was too low for therapy.
Mishima (Proc. 1st Int. Symp. NCT, 355, 1984) has reported the treatment of melanoma in swine with neutron irradiation following peritoneal injection of a total of 10 g BPA.
Boronated thioureas, especially thiouracil derivatives, have been proposed for NCT by Fairchild (Cancer Res., 42, 5126, 1982). However, except for some attempted syntheses by Wilson (Australia-Japan Workshop on Neutron Capture Therapy for Malignant Melanoma, 1986) no boronated analogue has been described in the literature. The major difficulty in synthesizing such derivatives lies in the properties of the dihydroxylboryl group, which is easily cleaved off organic molecules by acids as well as alkali. The dihydroxyboryl group has been introduced into NCT by Schinazi and Prusoff (Tetrahedron Lett., 50, 4981, 1978; J. Org. Chem., 50, 841, 1985).
The aim of the present invention is to provide stable boron-containing thiourea derivatives for neutron capture therapy, and to give procedures for their syntheses.